JP2012522834A - Pharmaceutical composition for the treatment or prevention of burn injury - Google Patents

Abstract

  The present invention relates to a pharmaceutical composition for the treatment of burns, and is characterized by containing a compound represented by a specific chemical formula or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. Accordingly, the present invention provides a therapeutic composition for burns containing these compounds or pharmaceutically acceptable salts or solvates thereof as active ingredients, and these compounds or pharmaceutically acceptable salts or solvents thereof. To provide a method for treating burns including administering a Japanese product to an object in need of burn treatment.

Description

  The present invention relates to a pharmaceutical composition useful for the treatment or prevention of damage caused by burns (burns / burns) and a method for treating or preventing burns (burns / burns).

  Burns are mainly caused by accidents, and can be classified into burns due to heat, burns due to electric current, burns due to chemical substances, and burns due to radiation depending on the cause. The severity of the burn is divided into 1 degree, 2 degrees, 3 degrees and 4 degrees burn according to the size and depth of the burned area, the temperature and contact time of the object that caused the burn, and the skin condition. Two burns can leave scars and require hospital treatment.

  A single burn causes the skin to become red and painful, such as irritation. It may cause damage to the epidermis, the outermost layer of the skin layer, and may swell up with pain and erythema. Symptoms disappear within a few days, but light desquamation and pigmentation may remain in the area. There is no scarring after recovery. Sunburn is the most common example of a single burn.

  Two burns affect both the epidermis and dermis, causing erythema, pain, swelling, and blistering within 24 hours after the accident. This burn can also affect sweat glands and pores. Subjectively, burning and pain are severe. If the water bubble breaks, it shows a erosion surface and a large amount of secretion comes out. Care must be taken especially when the burned area reaches about 15% or more of the body surface area. Heals within a few weeks, but pigmentation and depigmentation often remain in the area. If secondary infection occurs, local symptoms become more severe and last longer.

  Third-degree burns affect the epidermis, dermis, and even under the skin, causing the skin to darken or become translucent white, causing the blood vessels just below the skin surface to coagulate. The area of the burn may be numb, but the patient feels severe pain, necrotic skin tissue and structure, which takes time to treat and leaves scars later. Two weeks after the accident, the scab peels off and an ulcer surface appears. Although it has a lot of secretion and tends to bleed, new tissues gradually form, the epidermis regenerates, and scars remain and heal. When skin necrosis is deep or secondary infection occurs, treatment is delayed and the surface of the scar becomes irregular, causing keloids, deformation, and movement disorders. Special care is required when the burned area is 10% or more of the body surface area.

  A fourth-degree burn is a case where the burned tissue has been carbonized and turned black, and it has burned to the fat layer, ligament, fascia, muscle, bone tissue, etc. under the skin layer. . It is mainly caused by burns caused by high-voltage electricity, and in some cases, it may occur when bacteria are infected with a deep burn of 2 to 3 degrees. If the burn range is 20% or more, a systemic physical reaction may occur, but hypotension, shock, acute renal failure, etc. associated with excessive fluid loss may occur, followed by wound infection, pneumonia, sepsis Multiple organ dysfunction syndrome may occur.

  When treating burns, it is important to heal early burn wounds or reduce the number of burns as soon as possible. The initial burn dressing is used to control infection and inflammation, maintain a moist environment, administer growth factors and cytokines that help regenerate the skin, and use local heparin to prevent the transition to deep burns. Has been.

  Given the severity of these burn injury, if therapeutics are developed that are useful in the treatment or prevention of burn injury, it will be of great help in treating burn patients, improving their condition and reducing scars.

  Thus, the technical problem that the present invention seeks to achieve is to provide a pharmaceutical composition useful for the treatment or prevention of burn injury and the medical use of such a composition.

  In order to achieve the above technical problem, the present invention comprises a tetrafluorobenzyl derivative represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof, or treatment or prevention of burns: Pharmaceutical compositions for use are provided.

In the above chemical formula 1,
In Formula 1 above, R ₁ , R ₂ , and R ₃ are each independently hydrogen or halogen;
R ₄ is hydroxy, alkyl, alkoxy, halogen, alkoxy substituted with halogen, alkanoloxy or nitro;
R ₅ is a carboxylic acid, a carboxylic acid substituted with an alkyl group, a carboxylic acid amide, a sulfonic acid, halogen or nitro.

  That is, the present invention provides a pharmaceutical composition and a pharmaceutical use of the above tetrafluorobenzyl derivative and a pharmaceutically acceptable salt or solvate thereof for the treatment or prevention of burn injury.

  In the above chemical formula 1, alkyl is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 or 3 carbon atoms. Specifically, the alkyl is preferably a methyl, ethyl, propyl, isopropyl, butyl, secondary-butyl or tertiary-butyl group, but is not limited thereto. Alkoxy is preferably alkoxy having 1 to 5 carbon atoms, more preferably alkoxy having 1 or 3 carbon atoms. Specifically, the above alkoxy is preferably a methoxy, ethoxy or protooxy group, but is not limited thereto. Halogen is preferably fluorine, chlorine, bromine and iodine, but is not limited thereto. The alkanoyl is preferably an alkanol having 2 to 10 carbon atoms, and more preferably an alkanol having 2 or 5 carbon atoms. Specifically, as the above-mentioned alkanol, ethanenoyl, propanoyl, and cyclohexancarbonyl are preferable, but not limited thereto. The alkanoloxy is preferably an alkanoloxy having 1 to 4 carbon atoms.

  A preferred example of the tetrafluorobenzyl derivative represented by Formula 1 is 2-hydroxy-5- (2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid (2-Hydroxy). -5- (2,3,5,6-tetrafluoro-4-benzoylamino) -benzoicacid) (hereinafter referred to as “2-hydroxy-TTBA”), 2-nitro-5- (2,3,5, 6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid (2-Nitro-5- (2,3,5,6-tetrafluoro-4-benzoylamino) -benzoicacid), 2-chloro-5 -(2,3,5,6-tetrafluoro -4-trifluoromethyl-benzylamino) -benzoic acid (2-Chloro-5- (2,3,5,6-tetrafluoro-4-benzoylamino) -benzoicacid), 2-bromo-5- (2, 3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid (2-Bromo-5- (2,3,5,6-tetrafluoro-4-benzoylamino) -benzoicacid), 2 -Hydroxy-5- (2,3,5,6-tetrafluoro-4-methylbenzylamino) -benzoic acid (2-Hydroxy-5- (2,3,5,6-tetrafluoro-4-methyl-benzylamino) -Benzoi acid), 2-methyl-5- (2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid (2-Methyl-5- (2,3,5,6-tetrafluoro) -4-trifluoromethyl-benzylamino) -benzoicacid), 2-methoxy-5- (2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid (2-Methoxy-5- (2 , 3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoicacid) or 5- (2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -2-trifluoromethoxybenzoic acid Acid (5- (2,3,5,6-Tet afluoro-4-trifluoromethyl-benzylamino) -2-trifluoromethoxybenzoicacid) including, but not limited thereto.

  In the present invention, a burn generally refers to a phenomenon in which skin cells are destroyed or necrotized by heat. For example, a burn due to a fire, a hot water burn caused by a hot liquid (water, oil, etc.), a hot object (an electric iron) Including, but not limited to, contact burns due to contact with rice cookers, chemical burns due to strong acids, strong alkalis, etc., other sunburns caused by strong ultraviolet rays in summer, and radiation burns due to radiation and X-ray exposure. . Also, the burns of the present invention can be 1 degree, 2 degree, 3 degree or 4 degree burns.

  The tetrafluorobenzyl derivative of formula 1 and the pharmaceutically acceptable salts or solvates thereof according to the present invention can be used for the treatment or prevention of damage caused by these burns. It is not limited to the type or degree of burn (severity).

  The tetrafluorobenzyl derivative of the present invention or a pharmaceutically acceptable salt thereof can be produced by the production method disclosed in US Pat. No. 6,927,303. It is not limited to.

  For the compounds according to the invention, some compounds can be administered in the form of pharmaceutically acceptable salts. “Pharmaceutically acceptable salt” refers to a salt prepared with an acid or base with little or no toxicity. When the compound of the present invention is relatively acidic, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base with a suitable inert solvent. . Pharmaceutically acceptable base addition salts include, but are not limited to, salts composed of lithium, sodium, potassium, calcium, ammonium, magnesium, or organic amino. If the compound of the present invention is relatively basic, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid with a suitable inert solvent. Pharmaceutically acceptable acid addition salts include propionic acid, isobutyric acid, oxalic acid, malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid , P-Tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, hydrochloric acid, bromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid , Salts formed with hydrogen iodide, phosphorous acid, and the like, but are not limited thereto. Also included are, but are not limited to, salts of amino acids such as alginate and similar salts of organic acids such as glucuronic or galacturonic acid.

  The present invention also includes solvates, particularly hydrate forms, of the above compounds, and includes not only solvated forms (eg, hydrates) but also unsolvated forms. The compounds of the invention may also exist in crystalline or amorphous form, and all these physical forms are included within the scope of the invention. In addition, the compound of the present invention may have an asymmetric carbon atom or double bond at the optical center depending on the compound, and there exist racemates, enantiomers (enantiomers), diastereomers, geometric isomers, and the like. These are also within the scope of the present invention.

  The present invention also provides a pharmaceutical composition comprising the above compound or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient or additive. A compound of the present invention or a pharmaceutically acceptable salt / solvate thereof can be administered alone or in admixture with some convenient carriers, excipients, etc. The dosage form can be a single dose or a multiple dose dosage form.

  The pharmaceutical composition of the present invention can be a solid preparation or a liquid preparation. Solid preparations include, but are not limited to, powders, granules, tablets, capsules, suppositories and the like. Solid formulations can include, but are not limited to, excipients, flavoring agents, binders, preservatives, disintegrants, lubricants, fillers, and the like. Liquid formulations include water, solutions such as propylene glycol solutions, suspensions, emulsions, etc., but are not limited to these, and appropriate colorants, flavoring agents, stabilizers, thickeners. Etc. can be added.

  For example, a powder can be produced by simply mixing the tetrafluorobenzyl derivative compound of the present invention and a suitable pharmaceutically acceptable excipient such as lactose, starch, microcrystalline cellulose and the like. The granule is prepared by mixing the tetrafluorobenzyl derivative of the present invention; a suitable pharmaceutically acceptable excipient, and a suitable pharmaceutically acceptable binder such as polyvinylpyrrolidone and hydroxypropylcellulose. It can be produced using a wet granulation method using a solvent such as water, ethanol, isopropanol, or a dry granulation method using a compressive force. A tablet can be produced by mixing the above granule with a suitable pharmaceutically acceptable lubricant such as magnesium stearate and then tableting using a tableting machine.

  The pharmaceutical composition of the present invention can be used as an oral preparation, injection (for example, intramuscular injection, intraperitoneal injection, intravenous injection, infusion, subcutaneous injection, implant depending on the disease to be treated and the condition of the object. ), Inhalants, nasal drops, preparations applied to the vagina, preparations applied to the rectum, sublingual tablets, transdermal preparations, topical preparations, etc., but are not limited thereto . Depending on the route of administration, it can be formulated into a suitable dosage unit form, including non-toxic, pharmaceutically acceptable carriers, additives, and vehicles. Depot dosage forms that are capable of sustained drug release for a period of time are also within the scope of the present invention.

  The invention also includes administering a therapeutically effective amount of a compound of Formula 1 above, a pharmaceutically acceptable salt or solvate thereof to an object in need of treatment or prevention of burn injury. Provide a way to treat or prevent burn injury.

  In use for the treatment of burn injury, the compounds of the invention or pharmaceutically acceptable salts or solvates thereof can be administered from about 0.1 mg / kg to about 1000 mg / kg daily, A daily dose of 2.5 mg / kg to about 500 mg / kg is desirable. However, the dosage may vary depending on the patient's condition (age, sex, weight, etc.), the severity of the condition being treated, the compound used, etc. If necessary, the total daily dose can be divided for convenience and divided into multiple doses per day.

  The present invention provides a pharmaceutical composition useful for the treatment and prevention of burn injury characterized by comprising as an active ingredient the compound of Formula 1 above, a pharmaceutically acceptable salt or solvate thereof. The present invention also provides use of the compound of Formula 1 above, a pharmaceutically acceptable salt thereof, or a solvate for the treatment and prevention of burn injury. The present invention also includes administering a therapeutically effective amount of a compound of formula 1 above, a pharmaceutically acceptable salt or solvate to an object in need of treatment or prevention of burn injury. To provide a method for the treatment or prevention of damage caused by

It is a result of measuring the concentration of lactate dehydrogenase in serum by blood chemistry, and is a graph showing that 2-hydroxy-TTBA is effective in the treatment of burns. This is a photograph of the back skin observed on the seventh day after burn injury. When 2-hydroxy-TTBA is administered, it can be understood that burn damage is recovered relatively quickly. It is the result of the photograph which observed the state of the epithelial layer of the analysis tissue site | part by hematoxylin eosin (hematoxylin eosin) dyeing | staining. It is the result of the microscope picture which observed the state of the full-thickness structure | tissue of the stagnation zone (zone of tissue or zone of tissue injury) by hematoxylin eosin staining at 10-times magnification. It is the result of the micrograph which observed the living cell of the stagnation (zone of stasis or zone of tissue injury) skin tissue through cresyl violet dyeing | staining at 10 time magnification. It is the result of the microscope picture which observed the collagen (collagen) and the muscle fiber of the stagnant skin tissue through Masson'strichrom staining.

  Hereinafter, in order to help understanding of the present invention, examples will be described in detail. However, the embodiments according to the present invention can be modified in various forms, and the scope of the present invention should not be construed to be limited to the following embodiments. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the concept of the invention to those skilled in the art.

<Example 1> Therapeutic effect on burns caused by contact In order to verify the therapeutic effect of 2-hydroxy-TTBA on burns, a bronze comb preheated with boiling water (maintained at 100 ° C) for 3 minutes was used. Then, burns were induced by contact on both sides of the rat's back skin for 30 seconds. Five minutes later, 2-hydroxy-TTBA 10 mg / 5 ml / kg was intravenously injected over 5 minutes. Thereafter, the administration was continued in the same manner twice a day (at intervals of 10 to 12 hours) for a total of 7 days. In the vehicle administration group, only the same amount of physiological saline containing no drug was administered in the same manner. The experimental groups (Grouping of Rats for Burn experiments) are as shown in Table 1 below.

  Table 1 above shows the number of animals in the normal control group, the number of experimental animals in each group, and the number of individuals who died within 7 days after burn injury for comparison at the time of analysis of results. After the burn injury, two rats in the untreated burn control group died on days 5 and 7, respectively, and all the other experimental groups are all alive.

[Measurement of lactate dehydrogenase in serum by blood chemistry test]
Lactate dehydrogenase (LDH) is an enzyme that is distributed in almost all tissues and catalyzes the reversible conversion between pyruvic acid and lactic acid. . It is known that when tissues and cells are destroyed, they flow into the blood and LDH in the blood rises. For this reason, the amount of LDH between each group was investigated from the serum excluding the hemolyzed specimen that might interfere with the test. The results are shown in FIG.

  As shown in FIG. 1, in the burn control group, LDH increased about 2-fold compared to the normal control group, and LDH significantly decreased in the 2-hydroxy-TTBA administration group compared to the burn control group.

[Appearance of burns 7 days after injury in experimental groups]
FIG. 2 is a photograph of the skin on the back on the seventh day after burn injury. Full thickness skin burns were induced in four 10 × 20 mm rectangles using a bronze comb preheated on both sides of the back of the rats of the experimental group. Two hours after induction, four pale-colored coagulation zones (zone of cohesion or zone of tissue necrosis) and three stagnation zones (zone of stasis of zone of injury) There has occurred. The coagulation zone is an irreversible cell damage site that cannot be recovered over time, and the stagnation zone is a site where cell necrosis progresses without any special treatment within 24-48 hours. It is a site where ischemia occurs due to continuous fibrin deposition, vasoconstriction, thrombus, etc. and cells can die.

  Therefore, in this experiment, in order to search for drug efficacy, the vest was worn for drug administration out of a total of 6 sites generated by one rat object in the stagnant zone, which is a wound conversion site. The remaining four parts (the rectangular part shown by the dotted line in the figure) except for the head near the place where it was being analyzed were analyzed.

  Similar to the results in the photograph in Fig. 2, in the burn control group, where no treatment was performed after the burn injury, scabs formed in the stagnation zone and became wounds, and the wounds were separated, and skin loss was observed. I did. Scab formation such as scab occurs relatively rarely in the vehicle and 2-hydroxy-TTBA administration group, especially in the 2-hydroxy-TTBA administration group, the hair grows even when observed with the naked eye. The skin condition was restored.

[Histological Appearance of Escher Formation and Wound Epidermis Formation]
FIG. 3 shows the results of comparison of the state of the epithelial layer by staining the analysis tissue site with hematoxylin and eosin for each group. As shown in FIG. 3, unlike the normal epithelial layer (indicated by the arrow) correctly aligned with healthy hair follicles observed in the normal control group, As a result, normal epithelial cells were not observed except for inflammatory cells, and it was confirmed that regeneration of the epithelial layer was advanced in the vehicle administration group and the 2-hydroxy-TTBA administration group. At this time, even when epithelial proliferation (Hyperplasma of epidermis) occurred more than the thickness of the normal epithelial layer, it could be observed. As a result of analyzing such a phenomenon, a total of 28 tissue sites for each group (4 stagnant sites of 7 mice per group) were measured for the formation of crust and the frequency of epithelial layer regeneration. The frequency of wound conversion of about 93% in the burn group decreased to about 18% and 4% in the vehicle administration group and the 2-hydroxy-TTBA administration group, respectively. Also, when the regenerative epithelial layer was observed, it increased to about 32% and 71%, respectively, compared with the burn control group. The results are shown in Table 2 below (Histological appearance: scab formation and epithelial layer regeneration frequency).

[Histology of Full Tickness Stained by Hematoxylin and Eosin]
FIG. 4 is a photograph of the state of the full-thickness skin tissue in the stagnant band observed with a 10 × microscope using hematoxylin and eosin staining. In the burn control group, it was found that all layers of the epithelial layer, dermis layer, subcutaneous tissue and muscle layer were damaged, forming a scab and infiltrating inflammatory cells underneath, between the subcutaneous tissue and muscle. It was possible to observe the presence of many inflammatory cells. The vehicle-administered group did not form a scab-like scab, but a considerable amount of inflammatory cells were observed in the whole skin and subcutaneous tissues, and many inflammatory cells still infiltrated under the regenerated epithelial layer It was. In the 2-hydroxy-TTBA administration group, the infiltration of inflammatory cells is considerably suppressed except for the site of muscle cells and subcutaneous tissue layers. In addition to epithelial regeneration, in hair follicles, sebaceous glands, and muscle layers, A protective effect was observed.

[Histology of Full Thickness Stained by Cresyl Violet]
FIG. 5 is a photograph of living cells of stagnant tissue observed with a 10 × microscope through cresyl violet staining. In the burn control group and the vehicle-administered group, almost no hair follicles were observed, and a large amount of inflammatory cells were observed throughout the skin, whereas in the 2-hydroxy-TTBA-administered group, An epithelial layer was observed, and relatively few inflammatory cells were observed.

[Histology of Full Tickness Stained by Masson's trichrome] [Histology of Full Tickness Stained by Masson's trichrom]
FIG. 6 shows the results of micrographs in which collagen and myofibers in stagnant skin tissue were observed through Masson's trichrome staining. In the normal control group, the blue collagen was evenly distributed throughout the dermis layer and the muscle fibers were stained red.In the burn control group, the collagen was irregularly deposited under the scab. The degree of staining was also relatively weak compared to normal. Myofibers were also hardly damaged and stained. In the vehicle-treated group, the highest amount of collagen was observed compared to the other groups, which was very high compared to the normal control group. It was also observed that the muscle fibers were damaged and not stained, or were accompanied by significant amounts of bleeding and inflammatory cell infiltration. However, in the 2-hydroxy-TTBA administration group, as in the normal control group, it appears divided into the epithelial layer, dermis layer, subcutaneous fat, and muscle layer, and collagen is evenly distributed around the living hair follicle. The fibers also appeared red stained.

Claims (6)

A pharmaceutical composition for treating or preventing burn injury, comprising as an active ingredient a tetrafluorobenzyl derivative represented by the following chemical formula 1, or a pharmaceutically acceptable salt or solvate thereof:
In Formula 1 above, R ₁ , R ₂ , and R ₃ are each independently hydrogen or halogen; R ₄ is hydroxy, alkyl, alkoxy, halogen, alkoxy substituted with halo, alkanoloxy or nitro R ₅ is a carboxylic acid, a carboxylic acid substituted with an alkyl group having 1 to 4 carbon atoms, a carboxylic acid amide, a sulfonic acid, a halogen, or nitro.   The above tetrafluorobenzyl derivatives are 2-hydroxy-5- (2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid, 2-nitro-5- (2,3, 5,6-Tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid, 2-chloro-5- (2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid 2-Bromo-5- (2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid, 2-hydroxy-5- (2,3,5,6-tetrafluoro- 4-methylbenzylamino) -benzoic acid, 2-methyl-5- (2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid, 2-methoxy-5- (2, 3, 5 6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid, and 5- (2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -2-trifluoromethoxy-benzoic acid The pharmaceutical composition according to claim 1, wherein the composition is any one or more selected from the group consisting of acids.   3. The tetrafluorobenzyl derivative is 2-hydroxy-5- (2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid. Pharmaceutical composition. A therapeutically effective amount of the tetrafluorobenzyl derivative represented by Formula 1 above, or a pharmaceutically acceptable salt or solvate thereof, is administered to an object in need of treatment or prevention of burn injury. How to treat or prevent burn injury characterized by:
In Formula 1 above, R ₁ , R ₂ , and R ₃ are each independently hydrogen or halogen; R ₄ is hydroxy, alkyl, alkoxy, halogen, alkoxy substituted with halogen, alkanoloxy, Or nitro; R ₅ is a carboxylic acid, a carboxylic acid substituted with an alkyl group having 1 to 4 carbon atoms, a carboxylic acid amide, a sulfonic acid, a halogen, or nitro.   The above tetrafluorobenzyl derivatives are 2-hydroxy-5- (2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid, 2-nitro-5- (2,3, 5,6-Tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid, 2-chloro-5- (2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid 2-Bromo-5- (2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid, 2-hydroxy-5- (2,3,5,6-tetrafluoro- 4-methylbenzylamino) -benzoic acid, 2-methyl-5- (2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid, 2-methoxy-5- (2, 3, 5 6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid, and 5- (2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -2-trifluoromethoxybenzoic acid The method according to claim 4, wherein the method is at least one selected from the group consisting of: 6. The tetrafluorobenzyl derivative according to claim 5, which is 2-hydroxy-5- (2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) -benzoic acid. Method.